Dysfunctional Orexin-Regulated Neural Circuits in Alzheimer's Disease

阿尔茨海默病(AD)患者会在疾病早期出现空间定向障碍 进程。在人类和啮齿动物阿尔茨海默病模型中，脾后皮质(RSC)功能障碍是一个关键的 空间导航和记忆的位置，是在认知衰退开始之前观察到的。了解 RSC功能障碍的潜在机制对于制定旨在改善空间状况的策略非常重要 AD中的导航和记忆。我们观察到RSC网络活动异常，包括RSC节律降低 阿尔茨海默病小鼠模型在空间导航过程中的同步性，但其细胞和分子基础 缺陷是未知的。在这里，使用新开发的小鼠品系，我们鉴定了RSC的特定种群 表达食欲素1受体(RSCOX1R)并被神经肽食欲素激活的神经元。在西雅图 小鼠，直接刺激这些RSCOX1R神经元可以增强RSC的同步性，表明这些神经元是一种 研究AD相关RSC功能障碍的细胞机制的重要人群，并针对 治疗性干预。食欲素信号影响许多生理过程，包括空间记忆， 食欲素信号的异常参与了AD的病理过程。食欲素调节的特异性研究 然而，AD中缺乏存储电路。在这个提议中，我们研究了RSCOX1R神经元是否直接 在AD的5xFAD模型中改变(目标1)。我们还检验了RSCOX1R神经元的激活 或增强RSC神经元的增食欲素信号/调节可恢复RSC中AD相关的缺陷 节奏性活动(目标2)。这项工作的完成将为更大规模的后续研究铺平道路。 多种AD模型，有可能识别新的RSC和基于增食欲素的疗法，旨在 改善AD患者的一系列空间记忆和认知缺陷。

Persons with Alzheimer's Disease (AD) experience spatial disorientation that emerges early in the disease process. In both humans and rodent models of AD, dysfunction within the retrosplenial cortex (RSC), a crucial locus for spatial navigation and memory, is observed prior to the onset of cognitive decline. Understanding the mechanisms underlying RSC dysfunction is important to develop strategies aimed at improving spatial navigation and memory in AD. We observe aberrant RSC network activity that includes reduced RSC rhythmic synchrony during spatial navigation in a mouse model of AD, yet the cellular and molecular basis for these defects are unknown. Here, using a newly developed mouse line, we identify a specific population of RSC neurons that express the orexin 1 receptor (RSCOX1R) and are activated by the neuropeptide orexin. In WT mice, direct stimulation of these RSCOX1R neurons enhances RSC synchrony, suggesting these neurons are an important population in which to examine cellular mechanisms of AD-related RSC dysfunction, and to target for therapeutic intervention. Orexin signaling affects numerous physiologic processes, including spatial memory, and abnormalities in orexin signaling are implicated in AD pathology. Studies of specific orexin-regulated memory circuits in AD is lacking, however. In this proposal, we examine whether RSCOX1R neurons are directly altered in the 5xFAD model of AD (Aim 1). We also test the hypothesis that the activation of RSCOX1R neurons or enhancement of orexin-signaling/regulation of RSC neurons can restore the AD-associated deficits in RSC rhythmic activity (Aim 2). The completion of this work will pave the way for larger-scale follow up studies across multiple models of AD, with the potential to identify novel RSC and orexin-based therapies aimed at ameliorating a range of spatial memory and cognitive deficits in persons with AD.